Filamentous inclusions of tau protein are found in cases of inherited and sporadic frontotemporal dementias (FTDs). Mutations in MAPT, the tau gene, cause approximately 5% of cases of FTD. They proved that dysfunction of tau protein is sufficient to cause neurodegeneration and dementia. Clinically and pathologically, cases with MAPT mutations can resemble sporadic diseases, such as Pick's disease, globular glial tauopathy, progressive supranuclear palsy and corticobasal degeneration. The structures of tau filaments from Pick's disease and corticobasal degeneration, determined by electron cryo-microscopy, revealed the presence of specific tau folds in each disease, with no inter-individual variation. The same was true of chronic traumatic encephalopathy.Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative tauopathies with neuronal and glial lesions composed of tau that is composed predominantly of isomers with four repeats in the microtubule-binding domain (4R tau). The brain regions vulnerable to pathology in PSP and CBD overlap, but there are differences, particularly with respect to distribution of neuronal loss, the relative abundance of neuronal and glial lesions, the morphologic features of glial lesions, and the frequency of comorbid pathology. Both PSP and CBD have a wide spectrum of clinical manifestations, including disorders of movement and cognition. Recognition of phenotypic diversity in PSP and CBD may improve antemortem diagnostic accuracy, which tends to be very good for the most common presentation of PSP (Richardson syndrome), but poor for the most characteristic presentation of CBD (corticobasal syndrome CBS). Development of molecular and imaging biomarkers may improve antemortem diagnostic accuracy. https://www.selleckchem.com/mTOR.html Currently, multidisciplinary symptomatic and supportive treatment with pharmacological and non-pharmacological strategies remains the standard of care. In the future, experimental therapeutic trials will be important to slow disease progression.It is predictable that syndromes of frontotemporal dementia (FTD) may have a worldwide distribution; however, data available on their incidence and prevalence are variable. This variability most likely reflects disparities across regions in the distribution of the expertise, technology, and resources available for FTD research and care. Important discoveries have been made regarding FTD's phenotypes, genetics, and cultural influences on the expression of symptoms; however, in many countries, there are barriers posed by a dearth of resources. There are pressing needs to further develop research on FTD including first, population studies designed to fill the gaps in our knowledge about FTD's frequency and risk factors in developing regions and among minority groups in developed countries. It is also necessary to facilitate the psychometric characterization of contemporary diagnostic criteria and their translation to different languages and cultural contexts. Furthermore, much needed is the analysis of differences in the genetic risk factors for FTD, particularly non-Mendelian susceptibility factors. It is hoped that reflections on FTD from an international perspective will spur an extension of the vibrant multicenter collaborations, that exist in North America and Europe, toward new centers to be established and supported in the developing regions of the world.A timely diagnosis of frontotemporal degeneration (FTD) is frequently challenging due to the heterogeneous symptomatology and poor phenotype-pathological correlation. Fluid biomarkers that reflect FTD pathophysiology could be instrumental in both clinical practice and pharmaceutical trials. In recent years, significant progress has been made in developing biomarkers of neurodegenerative diseases amyloid-β and tau in cerebrospinal fluid (CSF) can be used to exclude Alzheimer's disease, while neurofilament light chain (NfL) is emerging as a promising, albeit nonspecific, marker of neurodegeneration in both CSF and blood. Gene-specific biomarkers such as PGRN in GRN mutation carriers and dipeptide repeat proteins in C9orf72 mutation carriers are potential target engagement markers in genetic FTD trials. Novel techniques capable of measuring very low concentrations of brain-derived proteins in peripheral fluids are facilitating studies of blood biomarkers as a minimally invasive alternative to CSF. A major remaining challenge is the identification of a biomarker that can be used to predict the neuropathological substrate in sporadic FTD patients.Around one-third of frontotemporal dementia (FTD) is autosomal dominant with the major genetic causes being mutations in MAPT, GRN and C9orf72. Studying familial forms of FTD can provide a window into the earliest stages of the illness, many years before symptoms start. Large cohort studies have been set up in recent years to better understand this presymptomatic phase, including the Genetic FTD Initiative (GENFI) and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (ARTFL/LEFFTDS) studies. Whilst these studies have focused on the investigation of a variety of aspects of genetic FTD, from understanding the molecular pathogenesis to developing biomarkers, they also have a common goal finding a way to prevent FTD. Researchers from these cohort studies have therefore come together to form the FTD Prevention Initiative (FPI), which has the overarching aim of promoting clinical trials of new therapies to prevent FTD through creating an international database of participants eligible for trials and uniform standards for conducting such trials. This chapter outlines the work of the FPI so far and its future goals over the next few years.Frontotemporal lobar dementia (FTLD) is a clinically and pathologically complex disease. Advances in neuroimaging techniques have provided a specialized set of tools to investigate underlying pathophysiology and identify clinical biomarkers that aid in diagnosis, prognostication, monitoring, and identification of appropriate endpoints in clinical trials. In this chapter, we review data discussing the utility of neuroimaging biomarkers in sporadic FTLD, with an emphasis on current and future clinical applications. Among those modalities readily utilized in clinical settings, T1-weighted structural magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) are best supported in differential diagnosis and as targets for clinical trial endpoints. However, a number of nonclinical neuroimaging modalities, including diffusion tensor imaging and resting-state functional connectivity MRI, show promise as biomarkers to predict progression and as clinical trial endpoints. Other neuroimaging modalities, including amyloid PET, Tau PET, and arterial spin labeling MRI, are also discussed, though more work is required to establish their utility in FTLD in clinical settings.